Aspartic proteases have the longest recorded history in all of enzymology, and perhaps the most perplexing. The earliest reported aspartic protease is pepsin. Pepsin is also likely to be the first enzyme recognized as an active principle (in 1783) and given a name (in 1825). Pepsin is only the second enzyme to be extracted (in 1836) and the second enzyme to be crystallized (in 1930).1, 2 
Extracts of pepsin have to be acidified to regain full activity, with different acids giving different results. Sörensen noted that if activities were plotted against hydrogen ion concentrations, the results were similar.3 (By way of historical footnote, to solve his scaling problem, Sörensen employed a logarithmic abscissa—and thus invented pH).
In addition to their catalytic functionality (hydrolytic cleavage of protein and peptide substrates), the identifying characteristic of aspartic proteases is their wide bell-shaped pH profiles with acidic optima. This peculiar characteristic has never been fully accounted for despite being featured in Sörensen's 1909 report of pH-dependent kinetics. That long unaccounted for peculiarity is without precedent in enzymology and, moreover, is joined with other seemingly unrelated uncertainties.
For example, how can transpeptidation reactions involving both halves of a peptide substrate (implying covalent acyl- and amino-enzyme intermediates) be explained? The parallel existence of acyl- and amino-enzyme intermediates within a single enzymatic mechanism seemed unlikely.4 
In the last two decades new uncertainties arose regarding aspartic proteases, most notably anomalous isotope effects. The discovery of these isotope effects was driven in large measure by the clinical significance of the HIV proteases. As the search for mechanism-based aspartic protease inhibitors for use in treating AIDS gained momentum, the mechanistic peculiarities of aspartic proteases came to the fore.
An excellent review of the current knowledge regarding aspartic proteases can be found in Meek.6 
In a notable recent paper, an ab initio study of free HIV-1 protease by Piana & Carloni5, the authors describe the presence of a low-barrier hydrogen bond within the active site of HIV-1 protease (an aspartic protease). As described below, determining the presence or absence of this low-barrier hydrogen bond when the aspartic protease is exposed to a known or putative aspartic protease inhibitor can serve as an excellent means to predict the efficacy of the inhibitor. Thus, the present invention is drawn to a method for evaluating the inhibition of aspartic proteases based upon the presence, absence, and electronic character of the low-barrier hydrogen bond present in the active site of all aspartic proteases.